Tumour architecture shapes polarized epithelial states that predict survival in high-grade serous ovarian cancer
Epithelial heterogeneity defines high-grade serous ovarian carcinoma (HGSC), yet principles that generate this diversity within and across tumours remain unclear. Integrating single-cell RNA sequencing (scRNA-seq) data from 13 studies (1,980,703 cells, 371 samples), we resolve a dominant axis of secretory cell polarization spanning proliferative, progenitor-like SecA cells and quiescent SecB cells expressing a mucosal injury response program. Targeted spatial transcriptomics across 8 whole HGSC tissues and a 97-patient tissue microarray shows this axis is spatially deterministic: tumour architecture shapes a hypoxic gradient along which SecB cells localize to avascular, luminal regions, where HIF/NF-{kappa}B-driven survival and glycolysis displace the mitogenic signalling of SecA. Within this niche, SecB cells rewire adhesion, ECM-remodelling, and immune-regulatory programs. Transcriptionally reprogrammed macrophages are enriched in this niche, while lymphocytes are excluded or dysfunctional. These cells assemble a coordinated multicellular niche poised for dissemination. SecB cells are enriched both in ascites and after chemotherapy, and are progressively lost in patient-derived organoids, only partially restored by IFN{gamma}, suggesting SecB is environmentally programmed rather than clonally fixed. SecB proportion independently predicts worse overall (HR = 1.31, p = 0.023) and progression-free survival (HR = 1.28, p = 0.011). Tumour architecture is thus a primary axis of malignant identity in HGSC, coupling microenvironment, cell state, and immune niche to clinical outcomes.